SUN Yue, ZHANG Wenlong, LI Nan, et al. Effect of Ursolic Acid Extracted from Hippophae rhamnoides L. on FXR Signaling Pathway in Liver of Rats with Alcoholic Liver Injury[J]. Science and Technology of Food Industry, 2023, 44(5): 363−370. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022040305.
Citation: SUN Yue, ZHANG Wenlong, LI Nan, et al. Effect of Ursolic Acid Extracted from Hippophae rhamnoides L. on FXR Signaling Pathway in Liver of Rats with Alcoholic Liver Injury[J]. Science and Technology of Food Industry, 2023, 44(5): 363−370. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022040305.

Effect of Ursolic Acid Extracted from Hippophae rhamnoides L. on FXR Signaling Pathway in Liver of Rats with Alcoholic Liver Injury

More Information
  • Received Date: April 26, 2022
  • Available Online: December 25, 2022
  • Objective: To investigate the effect of ursolic acid extracted from Hippophae rhamnoides L. on the expression of key proteins of hepatic farnesoid X receptor (FXR) signaling pathway in rats with alcoholic liver injury. Methods: The 6-week-old SPF SD rats were divided randomly into 4 groups: The normal control group, the alcohol model group, the ursolic acid control group and the ursolic acid+alcohol group, 9 mice in each group. The rats were administered by intragastric administration for eight consecutive weeks. The pathological changes of hepatic tissues in rats was observed by hematoxylin eosin (H&E) staining. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and the content of total bile acid (TBA) in serum, and the content of triglyceride (TG) and total cholesterol (TC) in liver of rats were tested. The content of the serum cytokine including tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 10 (IL-10) was detected by enzyme linked immunosorbent assay (ELISA). The expression of FXR signal pathway related proteins in liver tissue of rats was detected by Western blotting. Results: Compared with the normal control group, there were fat vacuoles of different sizes and a large number of inflammatory cells in the liver of the alcohol model group. The activities of ALT, AST, the levels of TNF-ɑ, IL-1β, the content of TBA in serum and the content of TG, TC in liver were increased significantly (P<0.05), and the level of IL-10 was decreased significantly (P<0.05). After the ursolic acid intervention, hepatic steatosis was improved significantly and inflammatory cell infiltration was decreased. The activities of ALT, AST, the levels of TNF-ɑ, IL-1β and the content of TBA in serum and the content of TG in liver were significantly decreased in different degrees (P<0.05), and the level of IL-10 was significantly increased (P<0.05). The Western blotting results showed that compared with the normal control group, the protein expression of FXR in the model group was decreased significantly (P<0.05), while the protein expression of CYP7A1 and SREBP-1c were increased significantly (P<0.05). After ursolic acid intervention, the protein expression of FXR expression was increased significantly, while the protein expression of CYP7A1 and SREBP-1c were decreased significantly, and the difference was statistically significant (P<0.05). Conclusion: The ursolic acid extracted from Hippophae rhamnoides L. can improve alcohol induced liver injury significantly, and its mechanism may be related to up regulating hepatic FXR, inhibiting the protein expression of CYP7A1 and SREBP-1c, thus regulating bile acid homeostasis and lipid metabolism.
  • [1]
    GAO B, SEKI E, BRENNER D A, et al. Innate immunity in alcoholic liver disease[J]. American Journal of Physiology Gastrointestinal and Liver Physiology,2011,300(4):516−525. doi: 10.1152/ajpgi.00537.2010
    [2]
    CRAUCIUC D V, STAN C I, RÎŞCANU L A, et al. Hepatic injuries resulting from chronic alcohol abuse identified by forensics[J]. Romanian Journal of Morphology and Embryology,2021,62(3):819−827. doi: 10.47162/RJME.62.3.20
    [3]
    SMAOUI S, HLIMA H B, MTIBAA A C, et al. Pomegranate peel as phenolic compounds source: Advanced analytical strategies and practical use in meat products[J]. Meat Science,2019,158:107914. doi: 10.1016/j.meatsci.2019.107914
    [4]
    KUBCZAK M, KHASSENOVA A B, SKALSKI B, et al. Hippophae rhamnoides L. leaf and twig extracts as rich sources of nutrients and bioactive compounds with antioxidant activity[J]. Scientific Reports,2022,12(1):1095. doi: 10.1038/s41598-022-05104-2
    [5]
    KU C M, LIN J Y. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes[J]. Food Chemistry,2013,141(2):1104−1113. doi: 10.1016/j.foodchem.2013.04.044
    [6]
    RAUDONE L, PUZERYTĖ V, VILKICKYTE G, et al. Sea buckthorn leaf powders: The impact of cultivar and drying mode on antioxidant, phytochemical, and chromatic profile of valuable resource[J]. Molecules (Basel, Switzerland),2021,26(16):4765.
    [7]
    SEO D Y, LEE S R, HEO J W, et al. Ursolic acid in health and disease[J]. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology,2018,22(3):235−248.
    [8]
    王丽聪. 高效液相测定沙棘果皮中熊果酸和齐墩果酸的含量[J]. 河北化工,2009,32(2):64−65. [WANG L C. Determination of ursolic acid and oleanolic acid in Hippophae rhamnoides L. peel by HPLC[J]. Hebei Chemical Industry,2009,32(2):64−65.
    [9]
    刘飙, 刘燕, 董明勤, 等. 熊果酸对周围神经损伤后BALB/c小鼠神经再生的影响[C]. 中华医学会第10届全国显微外科学术会议暨世界首例断肢再植成功50周年庆典论文集, 2013: 377

    LIU B, LIU Y, DONG M Q, et al. Effect of ursolic acid on nerve regeneration in BALB/c mice after peripheral nerve injury[C]. Proceedings of the 10th National Microsurgery Academic Conference of the Chinese Medical Association and the 50th Anniversary Celebration of the World's First Severed Limb Replantation, 2013: 377
    [10]
    ZHAO H, KONG L, SHAO M, et al. Protective effect of flavonoids extract of Hippophae rhamnoides L. on alcoholic fatty liver disease through regulating intestinal flora and inhibiting TAK1/p38MAPK/p65NF-κB pathway[J]. Journal of Ethnopharmacology,2022,292:115225. doi: 10.1016/j.jep.2022.115225
    [11]
    潘钰, 于冲, 夏海华, 等. 葛根素、姜黄素、沙棘黄酮复合物对乙醇致小鼠肝损伤的保护作用[J]. 黑龙江科学,2020,11(6):4−7. [PAN Y, YU C, XIA H H, et al. Protective effects of puerarin, curcumin and Hippophae rhamnoides L. flavone complex on ethanol induced liver injury in mice[J]. Heilongjiang Science,2020,11(6):4−7. doi: 10.3969/j.issn.1674-8646.2020.06.002
    [12]
    李可欣, 张男男, 侯瑞丽, 等. 沙棘熊果酸对酒精性肝病模型大鼠的保护作用[J]. 医药导报,2021,40(5):616−621. [LI K X, ZHANG N N, HOU R L, et al. Protective effect of the ursolic acid extracted from Hippophae rhamnoides L. on rats with alcoholic liver disease[J]. Medical Herald,2021,40(5):616−621.
    [13]
    杨冬晗, 贾逸林, 张文龙, 等. 基于TLR4信号通路探讨熊果酸改善大鼠酒精性肝损伤的作用机制[J]. 现代预防医学,2021,48(6):1099−1102, 1127. [YANG D H, JIA Y L, ZHANG W L, et al. Study on the mechanism of ursolic acid improving alcoholic liver injury in rats based on TLR4 signaling pathway[J]. Modern Preventive Medicine,2021,48(6):1099−1102, 1127.
    [14]
    WU W, ZHU B, PENG X, et al. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease[J]. Biochemical and Biophysical Research Communications,2014,443(1):68−73. doi: 10.1016/j.bbrc.2013.11.057
    [15]
    KONG B, ZHANG M, HUANG M, et al. FXR deficiency alters bile acid pool composition and exacerbates chronic alcohol induced liver injury[J]. Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Live,2019,51(4):570−576.
    [16]
    GENET C, STREHLE A, SCHMIDT C, et al. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: Potential impact in diabetes[J]. Journal of Medicinal Chemistry,2010,53(1):178−190. doi: 10.1021/jm900872z
    [17]
    KENICHI I, KUMIKO A, KAZUYOSHI K, et al. Ursolic acid ameliorates cholestatic liver injury caused by bile duct ligation in the rat[J]. Gastroenterology,2012,142(5):1025.
    [18]
    丁薇. 熊果酸经FXR调控OATP1B3的表达及其机制研究[D]. 南昌: 南昌大学, 2019

    DING W. Study on the expression and mechanism of OATP1B3 regulated by ursolic acid via FXR[D]. Nanchang: Nanchang University, 2019
    [19]
    鲁长征, 山永凯, 李树志, 等. 一种从沙棘中提取熊果酸的方法[P]. 青海: CN101817863A, 2010-09-01

    LU C Z, SHAN Y K, LI S Z, et al. A method for extracting ursolic acid from sea buckthorn[P]. Qinghai: CN101817863A, 2010-09-01.
    [20]
    张男男, 侯瑞丽, 李可欣, 等. 沙棘熊果酸对H22荷瘤小鼠抑瘤活性及其机制的探讨[J]. 食品研究与开发,2019,40(10):6−12. [ZHANG N N, HOU R L, LI K X, et al. Study on the antitumor activity and mechanism of the ursolic acid extracted from Hippophae rhamnoides L. in H22 tumor bearing mice[J]. Food Research and Development,2019,40(10):6−12. doi: 10.3969/j.issn.1005-6521.2019.10.002
    [21]
    GE N, LIANG H, ZHAO Y Y, et al. Aplysin protects against alcohol-induced liver injury via alleviating oxidative damage and modulating endogenous apoptosis-related genes expression in rats[J]. Journal of Food Science,2018,83(10):2612−2621. doi: 10.1111/1750-3841.14320
    [22]
    贾逸林, 杨冬晗, 李可欣, 等. 熊果酸对酒精诱导的大鼠小肠黏膜屏障损伤的保护作用[J]. 中国食品学报,2021,21(8):128−135. [JIA Y L, YANG D H, LI K X, et al. Protective effect of ursolic acid on alcohol induced intestinal mucosal barrier injury in rats[J]. Chinese Journal of Food,2021,21(8):128−135. doi: 10.16429/j.1009-7848.2021.08.012
    [23]
    DE SILVA N M G, BORGES M C, HINGORANI A D, et al. Liver function and risk of type 2 diabetes: Bidirectional mendelian randomization study[J]. Diabetes,2019,68(8):1681−1691. doi: 10.2337/db18-1048
    [24]
    TILG H, MOSCHEN A R, SZABO G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. Hepatology,2016,64(3):955−965. doi: 10.1002/hep.28456
    [25]
    KANG K, SUN Y, PAN D, et al. Distinctive gut microbial dysbiosis between chronic alcoholic fatty liver disease and metabolic-associated fatty liver disease in mice[J]. Experimental and Therapeutic Medicine,2021,21(5):418. doi: 10.3892/etm.2021.9862
    [26]
    李松鹏, 徐丽萍, 景红艳. 血清总胆汁酸测定在肝病诊断中的应用价值分析[J]. 中外医疗,2019,38(19):189−192. [LI S P, XU L P, JING H Y. Application value analysis of serum total bile acid in diagnosis of liver diseases[J]. Chinese and Foreign Medical Treatment,2019,38(19):189−192. doi: 10.16662/j.cnki.1674-0742.2019.19.189
    [27]
    HARTMANN P, HOCHRATH K, HORVATH A, et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice[J]. Hepatology,2018,67(6):2150−2166. doi: 10.1002/hep.29676
    [28]
    ORLICKY D J, ROEDE J R, BALES E, et al. Chronic ethanol consumption in mice alters hepatocyte lipid droplet properties[J]. Alcoholism, Clinical and Experimental Research,2011,35(6):1020−1033. doi: 10.1111/j.1530-0277.2011.01434.x
    [29]
    YU X, XUE M, LIU Y, et al. Effect of nicotinamide riboside on lipid metabolism and gut microflora-bile acid axis in alcohol-exposed mice[J]. Food Science & Nutrition,2021,9(1):429−440.
    [30]
    朱静宇, 王峻, 金秀娥, 等. 荞麦蜜对酒精诱导的小鼠肝损伤和肠道菌群失调的改善效果[J]. 华中农业大学学报,2021,40(5):169−178. [ZHU J Y, WANG J, JIN X E, et al. Effect of buckwheat honey on alcohol induced liver injury and intestinal flora imbalance in mice[J]. Journal of Huazhong Agricultural University,2021,40(5):169−178. doi: 10.13300/j.cnki.hnlkxb.2021.05.021
    [31]
    DONG Y, QIU P, ZHAO L S, et al. Metabolomics study of the hepatoprotective effect of Phellinus igniarius in chronic ethanol-induced liver injury mice using UPLC-Q/TOF-MS combined with ingenuity pathway analysis[J]. Phytomedicine:International Journal of Phytotherapy and Phytopharmacology,2020,74:152697. doi: 10.1016/j.phymed.2018.09.232
    [32]
    赵亚芳, 李郁茹, 陈玉民, 等. 王不留行炭纳米类成分发现及其对小鼠酒精性肝损伤保护作用[J]. 中草药,2021,52(22):6825−6833. [ZHAO Y F, LI Y R, CHEN Y M, et al. Discovery of carbon nano components of Wangbuliuxing and its protective effect on alcoholic liver injury in mice[J]. Chinese Herbal Medicine,2021,52(22):6825−6833. doi: 10.7501/j.issn.0253-2670.2021.22.007
    [33]
    周博宇, 孙兰, 隋自洁, 等. 香菇多糖对大鼠酒精性肝损伤的保护作用[J]. 中国卫生工程学,2022,21(1):54−56. [ZHOU B Y, SUN L, SUI Z J, et al. Protective effect of Lentinan on alcoholic liver injury in rats[J]. Chinese Health Engineering,2022,21(1):54−56.
    [34]
    LYU X C, WU Q, CAO Y J, et al. Ganoderic acid a from Ganoderma lucidum protects against alcoholic liver injury through ameliorating the lipid metabolism and modulating the intestinal microbial composition[J]. Food & Function,2022,13(10):5820−5837.
    [35]
    JIANG L, ZHANG H, XIAO D, et al. Farnesoid X receptor (FXR): Structures and ligands[J]. Computational and Structural Biotechnology Journal,2021,19:2148−2159. doi: 10.1016/j.csbj.2021.04.029
    [36]
    LI T, FRANCL J M, BOEHME S, et al. Glucose and insulin induction of bile acid synthesis: Mechanisms and implication in diabetes and obesity[J]. The Journal of Biological Chemistry,2012,287(3):1861−1873. doi: 10.1074/jbc.M111.305789
    [37]
    GADALETA R M, VAN ERPECUM K J, OLDENBURG B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease[J]. Gut,2011,60(4):463−472. doi: 10.1136/gut.2010.212159
    [38]
    ZHOU W, ANAKK S. Enterohepatic and non-canonical roles of farnesoid X receptor in controlling lipid and glucose metabolism[J]. Molecular and Cellular Endocrinology,2022,549:111616. doi: 10.1016/j.mce.2022.111616
    [39]
    WANG H, HE Q, WANG G, et al. FXR modulators for enterohepatic and metabolic diseases[J]. Expert Oinion on Therapeutic Patents,2018,28(11):765−782. doi: 10.1080/13543776.2018.1527906
    [40]
    FENG X H, DERYNCK R. Specificity and versatility in tgf-beta signaling through Smads[J]. Annual Review of Cell and Developmental Biology,2005,21:659−693. doi: 10.1146/annurev.cellbio.21.022404.142018
    [41]
    ZHANG Y, EDWARDS P A. FXR signaling in metabolic disease[J]. Febs Letters,2008,582(1):10−18. doi: 10.1016/j.febslet.2007.11.015
    [42]
    SAYIN S I, WAHLSTROM A, FELIN J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist[J]. Cell Metabolism,2013,17(2):225−235. doi: 10.1016/j.cmet.2013.01.003
    [43]
    GUO P Y, XUE M, TENG X, et al. Antarctic krill oil ameliorates liver injury in rats exposed to alcohol by regulating bile acids metabolism and gut microbiota[J]. The Journal of Nutritional Biochemistry,2022:109061.
    [44]
    SHIMANO H, SATO R. SREBP-regulated lipid metabolism: Convergent physiology-divergent pathophysiology[J]. Nature Reviews Endocrinology,2017,13(12):710−730. doi: 10.1038/nrendo.2017.91
    [45]
    GAO B, BATALLER R. Alcoholic liver disease: Pathogenesis and new therapeutic targets[J]. Gastroenterology,2011,141(5):1572−1585. doi: 10.1053/j.gastro.2011.09.002
    [46]
    LIVERO F A, STOLF A M, DREIFUSS A A, et al. The FXR agonist 6ECDCA reduces hepatic steatosis and oxidative stress induced by ethanol and low-protein diet in mice[J]. Chemico-biological Interactions,2014,217:19−27. doi: 10.1016/j.cbi.2014.03.014

Catalog

    Article Metrics

    Article views PDF downloads Cited by()

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return